Alterations in vascular tone are thought to contribute to ischemic heart disease, coronary vasospasm and hypertension. In recent years, the importance of the endothelial cell (EC) lining of the blood vessel in the regulation of vascular tone has become apparent. These vascular effects or ECs are attributed to a local hormone that is called endothelium derived relaxant factor (EDRF). There is now evidence for multiple EDRFs. One EDRF is nitric oxide (NO) (NO-EDRF). In addition, there is an EDRF released by arachidonic acid (AA-EDRF) that is not PGI2 but appears to be a lipoxygenase and/or cytochrome P450 metabolite since its release is blocked by inhibitors of these enzymes. Its identity has not been determined. Two endothelium-derived constrictor factors (EDCF) have also been described. One is the peptide endothelin, and the other is a cyclooxygenase metabolite of arachidonic acid. In pulmonary vessels, we have identified this latter AA-EDCF as the vasoconstrictor thromboxane (Tx) A2. The proposed studies will test the hypothesis that arachidonic acid is metabolized by the endothelium to vasodilator and vasoconstrictor metabolites that are involved in the regulation of vascular tone, contribute to the action of vasoactive hormones and may be involved in ischemic heart disease and hypertension. Using chemical, biochemical and pharmacological approaches, the proposed experiments will determine the chemical structure of AA-EDRF, characterize its synthesis and release and determine its biological importance in regulating vascular tone. Furthermore, experiments are proposed to characterize the synthesis of AA- EDCF and determine its role in regulating vascular tone. We propose to test the hypothesis further by investigating the following specific aims: (1) We have found that arachidonic acid is metabolized to an unknown metabolite by the rabbit aorta. The synthesis of this metabolite is inhibited by lipoxygenase inhibitors and removal of the endothelium and enhanced by cyclooxygenase inhibitors. The partially purified metabolite relaxes the pre-contracted rabbit aorta. We propose to identify this metabolite and investigate the regulation of its release and synthesis. The effects of the inhibitors will be determined. This information will determine the contribution of the metabolite to vascular tone and to the activity of vasoactive hormones. (2) We have identified an EDCF in the pulmonary vasculature as TxA2. Since pulmonary ECs do not synthesize TxA2, another cell associated with or adhering to the intima must be the source of the TxA2. Studies are proposed to determine the cellular source of the TxA2 and study the regulation of its synthesis. Other studies will investigate the interaction between the intimal cells in the synthesis of vasoactive substances. (3) We have identified a subset of rabbits that do not respond to EDCF or TxA2 agonists with a vasoconstrictor response. These animals are relatively deficient in vascular, but not platelet, TxA2/PGH2 receptors. Further studies are planned to characterize the cause of this reduction in receptor density and use these animals to determine the contribution of the vascular TxA2/PGH2 receptor in the regulation of vascular tone.
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